Cellular Basis Artemisinin Tender

Grant agreement ID 101021493Start date 1 December 2021End date 30 November 2026Overall budget 2 388 24250 ObjectiveBlood stages of the protozoan parasite Plasmodium falciparum are responsible for malaria a disease that kills more than 400000 people annually. During its development in red blood cells the parasite internalises a large part of the host cell cytosol hemoglobin in an endocytic process and digests it in its food vacuole. We recently identified a critical connection of this hemoglobin endocytosis with resistance of the parasite to the current frontline drug Artemisinin revealing the mechanism of resistance. Artemisinin is activated by hemoglobin degradation products and we found that Artemisinin resistant parasite endocytose less. Using a toolbox of recently established approaches to carry out functional studies in malaria parasites we identified an entire series of proteins involved in endocytosis that are involved in resistance to Artemisinin. This included Kelch13 the molecular marker of Artemisinin resistance in field samples. This provides us with a unique opportunity i to elucidate how these molecules orchestrate endocytosis a prominent essential process in these parasites that so far is not understood on a molecular level ii to specifically understand the role of Kelch13 in this process and in resistance and iii to elucidate the reason for the fitness cost that is associated with Artemisinin resistance and the compensatory mechanisms the parasite uses to mitigate them. We expect this research program to not only elucidate so far elusive key aspects of the cell biology of this important parasite but also to identify critical constraints of Artemisinin resistant parasites and possible ways to circumvent ART resistance.